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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2002 Sep;93(9):1029–1036. doi: 10.1111/j.1349-7006.2002.tb02480.x

Thalidomide for the Treatment of Refractory Multiple Myeloma: Association of Plasma Concentrations of Thalidomide and Angiogenic Growth Factors with Clinical Outcome

Tsunayuki Kakimoto 1, Yutaka Hattori 1,✉, Shinichiro Okamoto 1, Norihide Sato 1, Tamihiro Kamata 1, Masaya Yamaguchi 2, Kunihiko Morita 2, Taketo Yamada 3, Nobuyuki Takayama 1, Hideo Uchida 1, Naoki Shimada 4, Yusuke Tanigawara 2, Yasuo Ikeda 1
PMCID: PMC5927128  PMID: 12359057

Abstract

Recent reports showed that thalidomide has anti‐angiogenic activity and is effective for the treatment of refractory multiple myeloma (MM). We examined the relationship between the clinical efficacy and adverse effects of thalidomide and the plasma concentrations of this drug as well as angiogenic growth factors in refractory MM. Ten out of twenty‐four evaluable patients (42%) showed more than 25% reduction of M‐protein, and eight (33%) achieved more than 50% reduction. These changes were associated with restoration of anemia and recovery of normal immunoglobulin level. Somnolence and headache, constipation, peripheral neuropathy and skin rash were frequently observed, but were well tolerated. However, grade 2–4 severe neutropenia was also observed in nine cases. These adverse effects other than neutropenia occurred more frequently in the patients with higher plasma concentrations of thalidomide (≥2.0 μg/ml at 12 h after the last administration) and were readily alleviated by dose reduction. In contrast, neutropenia developed regardless of the plasma concentration. Plasma concentrations of angiogenic growth factors were frequently elevated before treatment. After thalidomide treatment, these growth factor levels tend to decrease to near‐normal ranges in responders but were still high in most non‐responders. After thalidomide treatment, plasma vascular endothelial growth factor (VEGF) level was significantly reduced in responders (P=0.025), but not in non‐responders (P=0.37). Reduction of plasma VEGF level might be an important indicator for anti‐myeloma effect of thalidomide.

Keywords: Thalidomide, Multiple myeloma, Fibroblast growth factor, Vascular endothelial growth factor, Neutropenia

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REFERENCES

  • 1. ) Alexanian , R. and Dimopoulos , M.The treatment of multiple myeloma . N. Engl. J. Med. , 330 , 484 – 489 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Wada , M. , Mizoguchi , H. , Kuriya , S. , Taguchi , H. , Kawamura , T. , Maekawa , L , Shimazaki , C. , Sato , Y. , Niho , Y. , Miyazaki , T. , Shibata , A. , Kitani , T. , Hamajima , N. and Ohno , R.and Japanese Co‐operative Study Group for the Treatment of Multiple Myeloma. Induction therapy consisting of alternating cycles of ranimustine, vincristine, melphalan, dexamethasone and interferon (ROAD‐IN) and a randomized comparison of interferon maintenance in multiple myeloma: a co‐operative study in Japan . Br. J. Haematol. , 109 , 805 – 814 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Harousseau , J. L. , Altai , M. , Divine , M. , Marit , G. , Leblond , V. , Stoppa , A. M. , Bourhis , J. H. , Caillot , D. , Boasson , M. , Abgrall , J. F. , Facon , T. , Linassier , C. , Cahn , J. Y. , Lamy , T. , Troussard , X. , Gratecos , N. , Pignon , B. , Auzanneau , G. and Bataille , R.Autologous stem cell transplantation after first remission induction treatment in multiple myeloma: a report of the French registry on autologous transplantation in multiple myeloma . Blood , 85 , 3077 – 3085 ( 1995. ). [PubMed] [Google Scholar]
  • 4. ) Attai , M. , Harousseau , J. L. , Stoppa , A. M. , Sotto , J. J. , Fuzibel , J. G. , Rossi , J. F. , Casassus , Ph. , Maisonneuve , H. , Facon , T. , Ifrash , N. , Payen , C. and Bataille , R.for the Inlergroupe Francaise du Myeloma. A prospective, randomized trial of autologous bone marrow transplanlalion and chemolherapy in multiple myeloma . N. Engl. J. Med. , 335 , 91 – 97 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Barlogie , B. , Jagannath , S. , Vesole , D. H. , Naucke , S. , Cheson , B. , Mattox , S. , Bracy , D. , Salmon , S. , Jacobson , J. , Crowley , J. and Tricot , G.Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma . Blood , 89 , 789 – 793 ( 1997. ). [PubMed] [Google Scholar]
  • 6. ) Barlogie , B. , Jagannath , S. , Desikan , K. R. , Mattox , S. , Vesole , D. , Siegel , D. , Tricot , G. , Munshi , N. , Fassas , A. , Singhal , S. , Mehta , J. , Anaissie , E. , Dhodapkar , D. , Naucke , S. , Cromer , J. , Sawyer , J. , Epstein , J. , Spoon , D. , Ayers , D. , Cheson , B. and Crowley , J.Total therapy with tandem transplants for newly diagnosed multiple myeloma . Blood , 93 , 55 – 65 ( 1999. ). [PubMed] [Google Scholar]
  • 7. ) Tseng , S. , Pak , G. , Washenik , K. , Pomeranz , M. K. and Shupak , J. L.Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses . J. Am. Acad. Dermatol. , 35 , 969 – 979 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) D'Amato , R. J. , Loughnan , M. S. , Flynn , E. and Folkman , J.Thalidomide is an inhibitor of angiogenesis . Proc. Natl. Acad. Sei. USA , 91 , 4082 – 4085 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. ) Baidas , S. M. , Winer , E. P. , Fleming , G. F. , Harris , L. , Pluda , J. M. , Crawford , J. G. , Yamauchi , H. , Isaacs , C. , Hanfelt , J. , Tefft , M. , Flockhart , D. , Johnson , M. D. , Hawkins , M. J. , Lippman , M. E. and Hayes , D. F.Phase II evaluation of thalidomide in patients with metastatic breast cancer . J. Clin. Oncol. , 18 , 2710 – 2717 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Fine , H. A. , Figg , W. D. , Jaeckle , K. , Wen , P. Y. , Kyritsis , A. P. , Loeffler , J. S. , Levin , V. A. , Black , P. M. , Kaplan , R. , Pluda , J. M. and Yung , W. K. A.Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high‐grade glioma . J. Clin. Oncol. , 18 , 708 – 715 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Gutheil , J. and Finucane , D.Thalidomide therapy in refractory solid tumour patients . Br. J. Haematol. , 110 , 754 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Vacca , A. , Ribiatti , D. , Roncali , L. , Ranieri , G. , Serio , G. , Silvestris , F. and Dommacco , F.Bone marrow angiogenesis and progression in multiple myeloma . Br. J. Haematol. , 87 , 503 – 508 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Vacca , A. , Ribiatti , D. , Roncali , L. and Dommacco , F.Angiogenesis in B cell lymphoproliferative diseases. Biological and clinical studies . Leuk. Lymphoma , 20 , 27 – 38 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Vacca , A. , Loreto , M. D. , Ribiatti , D. , Stefano , R. D. , Gadaleta‐Caldarola , G. , Lodice , G. , Caloro , D. and Dammacco , F.Bone marrow of patients with active myeloma: angiogenesis and plasma cell adhesion molecules LFA‐1, VLA‐4, LAM‐1, and CD44 . Am. J. Hematol. , 50 , 9 – 14 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Vacca , A. , Ribiatti , D. , Presta , M. , Minischetti , M. , Lurlaro , M. , Ria , R. , Albini , A. , Bussolino , F. and Dommacco , F.Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase‐2 secretion parallel progression of human multiple myeloma . Blood , 93 , 3064 – 3073 ( 1999. ). [PubMed] [Google Scholar]
  • 16. ) Sato , N. , Hattori , Y. , Du , W. , Yamada , T. , Kamata , T. , Kakimoto , T. , Okamoto , S. , Kawamura , C. , Kizaki , M. , Shimada , N. , Ote , Y. , Hata , J. and Ikeda , Y.Elevated level of plasma basic fibroblast growth factor in multiple myeloma correlates with increased disease activity . Jpn. J. Cancer Res. , 93 , 459 – 466 ( 2002. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Singhal , S. , Mehta , J. , Desikan , R. , Ayers , D. , Roberson , P. , Eddlemon , P. , Munshi , N. , Anaissie , E. , Wilson , C. , Dhodapkar , M. , Zeldis , J. and Barlogie , B.Anti‐tumor activity of thalidomide in refractory multiple myeloma . N. Engl. J. Med. , 341 , 1565 – 1571 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Alexanian , R. and Weber , D.Thalidomide for resistant and relapsing myeloma . Semin. Hematol. , 37 , 22 – 25 ( 2000. ). 10676920 [Google Scholar]
  • 19. ) Juliusson , G. , Celsing , F. , Turesson , I , Lenhoff , S. , Adriansson , M. and Malm , C.Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma . Br. J. Haematol. , 109 , 89 – 96 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Kneller , A. , Raanani , P. , Hardan , I , Avigdor , A. , Levi , I , Berkowicz , M. and Ben‐Bassat , I.Therapy with thalidomide in refractory multiple myeloma patients–‐the revival of an old drug . Br. J. Haematol. , 108 , 391 – 393 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Gore , M. E. , Selby , P. J. , Viner , C. , Clark , P. I , Meldrum , M. , Millar , B. , Bell , J. , Maitland , J. A. , Milan , S. , Judson , I. R. , Zuiable , A. , Tillyer , C. , Slevin , M. and Malpas , J. S.Intensive treatment of multiple myeloma and criteria for complete remission . Lancet , ii , 879 – 881 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Boughton , B. J. , Sheehan , T. M. T. , Wood , J. , O'Brien , D. , Butler , M. , Simpson , A. and Hale , K. A.High‐performance liquid chromatographic assay of plasma thalidomide: stabilization of specimens and determination of a tentative therapeutic range for chronic graft‐versus‐host disease . Ann. Clin. Biochem. , 32 , 79 – 83 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Durie , B. G. M. and Salmon , S. E.A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival . Cancer , 36 , 842 – 854 ( 1975. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Schreiber , S. , Ackermann , J. , Obermair , A. , Kaufmann , H. , Urbauer , E. , Aletaha , K. , Gisslinger , H. , Chott , A. , Huber , H. and Drach , J.Multiple myeloma with deletion of chromosome 13q is characterized by increased bone marrow neovascularization . Br. J. Haematol. , 110 , 605 – 609 ( 2000. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Larkin , M.Low‐dose thalidomide seems to be effective in multiple myeloma . Lancet , 354 , 925 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Osman , K. , Comenzo , R. and Rajikumar , S. V.Deep vein thrombosis and thalidomide therapy for multiple myeloma . N. Engl. J. Med. , 344 , 1951 – 1952 ( 2001. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Hideshima , T. , Chauhan , D. , Shima , Y. , Raje , N. , Davies , F. E. , Tai , Y. T. , Treon , S. P. , Lin , B. , Schlossman , R. L. , Richardson , P. , Muller , G. , Stirling , D. I. and Anderson , K. C.Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy . Blood , 96 , 2943 – 2950 ( 2000. ). [PubMed] [Google Scholar]
  • 28. ) Neben , K. , Moehler , T. , Egerer , G. , Kraemer , A. , Hillengass , J. , Benner , A. , Ho , A. D. and Goldschmidt , H.High plasma basic fibroblast growth factor concentration is associated with response to thalidomide in progressive multiple myeloma . Clin. Cancer Res. , 7 , 2675 – 2681 ( 2001. ). [PubMed] [Google Scholar]

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